Cancer is a leading cause of death worldwide accounting for 7.4 million deaths (around 13% of all deaths) in 2004 according to data of World Health Organization (WHO).
The main types of cancer leading to overall cancer mortality each year are: lung (1.3 million deaths/year), stomach (803000 deaths), colorectal (639000 deaths) and liver (610000 deaths).
Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030.
Some of the most common cancer types, such as breast cancer, cervical cancer and colorectal cancer, have high cure rates when detected early and treated according to best practice, but others still require continuous research to reach acceptable cure rates. Principal treatment methods to cure tumors are surgery, radiotherapy and chemotherapy.
Chemotherapy includes treatment, among others, with metal-based drugs such as cis-diamminodichloro platinum(II) (CDDP) and other platinum(II) drugs such as carboplatin and oxaliplatin (OXP).
CDDP is approved by the Food and Drug Administration (FDA) to be used by itself to treat: i) bladder cancer that cannot be treated with surgery or radiotherapy and ii) ovarian cancer that has metastasized and has not gotten better with other drugs. In addition, CDDP is approved to be used in combination with other drugs to treat: i) advanced and metastatic ovarian cancer and ii) testicular cancer.
The second generation platinum(H) drug OXP is FDA approved for adjuvant therapy for stage III colorectal cancer and for initial therapy of advanced colorectal cancer.
Although highly effective in treating a variety of cancers, the use of platinum(II) drugs is limited by several side effects including nephrotoxicity, emetogenesis and neurotoxicity, and the emerging of inherited and/or acquired resistance phenomena.
Ongoing from the first generation drug CDDP to second generation carboplatin and OXP compounds, the issues of reducing toxicity over normal cells and to widen the spectrum of action toward additional human cancers have been only partially addressed.
Moreover, platinum drugs are often endowed with poor water solubility. A long-standing need exists for metallodrugs having improved hydrophilic character to get a suitable solubility in physiological conditions. In the search of new therapies avoiding these drawbacks, other metals have been considered as alternatives to platinum. Complexes including iron, cobalt and gold have shown promising results in preclinical studies, whereas complexes with titanium, ruthenium and gallium have already been evaluated in phase I and phase II clinical trials, as reviewed by I. Ott and R. Gust, Arch. Pharm. Chem. Life Sci., 2007, 340, 117-126. Metal complexes may undergo both redox reactions and ligand substitution, which allow them to participate in a variety of biological redox chemistries and to interact with different biological substrates.
In this perspective, even more challenging is the use of essential metal ions, such as copper (Cu). Since copper, as essential metal which escapes its normal metabolic pathways can be toxic to the organism, copper complexes may have the potential to be effective cytotoxic agents.
The approach of using copper complexes as antitumor agents, mimicking the widespread clinical use of platinum metallodrugs, has extensively been investigated.
The chemical identity, number and geometry of the ligating groups determine the relative stabilities of the resulting Cu(I) and Cu(H) complexes.
Analysis of small-molecule copper chemistry generally indicates that Cu(I) binding is thermodynamically favored by the inclusion of more sulfur, phosphorus and sp2-nitrogen donors. As opposed, oxygen or sp3-nitrogen donors stabilize Cu(II) species. Easy accessibility of two-, three- and four-coordinate geometries is another feature typical of Cu(I), whereas Cu(II) is better stabilized in four-, five- and six-coordinated arrangements, as reviewed by C. Marzano, M. Pellei, F. Tisato and C. Santini, Anti-Cancer Agents in Medicinal Chemistry, 2009, 9, 185-211 and by F. Tisato, C. Marzano, M. Porchia, M. Pellei and C. Santini, Medicinal Research Reviews, 2010, 30, 708-749.
The choice of using copper complexes offers the opportunity to make use of a more physiological metal with the interesting perspective of adopting cytotoxic mechanisms of action different from those exhibited by CDDP, in order to widen the spectrum of antitumor activity and contemporarily reduce toxic side effects. However, although a large assortment of cytotoxic copper compounds has been proposed as antiproliferative agents, only few compounds showed the desired characteristics to be evaluated as possible antitumor agents. Among such compounds, bis(aryl)diphosphine (P—P) metal(I) complexes of the type [M(P—P)2][Cl] wherein M can be gold (Au), silver (Ag) or copper (Cu) and P—P can be 1,2-bis(diphenylphosphine)ethane (dppe), 1,2-bis(diphenylphosphine)propane (dppp), 1,2-bis(diphenylphosphine)ethylene (dppey), showed cytotoxic activity in vitro against P388 murine leukemia (S. J. Berners-Price, C. K. Mirabelli, R. K. Johnson, M. R. Mattern, F. L. McCabe, L. F. Faucette, C. M. Sung, S. M. Mong, P. J. Sadler and S. T. Crooke, Cancer Res., 1986, 46, 5486-5493), B16 melanoma and M5076 reticulum cell sarcoma.
However, the presence of several phenyl groups appended to the phosphorus donors in bis(aryl)diphosphine gold and isostructural copper compounds caused undesired nephrotoxicity (S. J. Bemers-Price, R. K. Johnson, C. K. Mirabelli, L. F. Faucette, F. L. McCabe and P. J. Sadler, Inorg. Chem., 1987, 26, 3383-3387) and cardiovascular toxicity (G. D. Hoke, R. A. Macia, P. C. Meunier, P. J. Bugelski, C. K. Mirabelli, G. F. Rush and W. D. Matthews, Toxicol. Appl. Pharmacol., 1989, 100, 293-306) in animal models, respectively, thus precluding clinical trials in humans.
Consequently, efforts have been devoted to the design of less lipophilic copper derivatives, as in the case of the partial substitution of the ‘CuP4’ aryldiphosphine coordination sphere with heterocyclic thiones (M. K. Adwankar, C. Wycliff and A. Samuelson, Indian. J. Exp. Biol., 1997, 35, 810-814), acetonitrile (N. J. Sanghamitra, P. Phatak, S. Das, A. G. Samuelson and K. Somasundaram, J. Med. Chem., 2005, 48, 977-985), and N-heterocycles such as carbazole and benzotriazole producing mixed-ligand type compounds.
Following a similar mixed-ligand approach, several scorpionate ligands attached to a ‘CuP2’ moiety, as disclosed by C. Marzano, M. Pellei, S. Alidori, A. Brossa, G. Gioia Lobbia, F. Tisato and C. Santini, J. Inorg. Biochem., 2006, 100, 299-304, wherein P2 is bidentate dppe or two monodentate aryl-phosphine, have been tested.
The use of dihydrobis(3-nitro-1,2,4-triazolyl)borate scorpionate ligands, [H2B (tzNO2)2], had the double aim at increasing the water solubility and the kinetic inertness of the resulting mixed-complexes. Chemosensitivity tests performed on CDDP sensitive and resistant human cancer cell lines established that [(scorpionate)Cu(thp)2] type compounds were able to overcome CDDP resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the reference drug CDDP. In particular, the compound [HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2 has demonstrated a significant antitumor activity in vitro, being active also against CDDP resistant cell lines.
However, this kind of mixed-ligand copper complexes is very difficult to synthesize and purify, and its cytotoxic potency is rather scarce.
The Italian Patent No. IT 1369596, which disclosure is herewith incorporated under reference, discloses copper(I) complexes with the ligand tris(hydroxymethyl)phosphine that confers an advantageous hydrophilic property to the corresponding Cu(I) compounds.
In the present invention, it is disclosed the use of hydrophilic phosphino Cu(I) complexes instead of lipophilic ones in order to avoid the toxicity problems. The hydrophilic feature is given by the choice of the hydrophilic tris(hydroxymethyl)phosphine (thp) ligand, which allows the preparation of perfectly aqueous soluble species (C. Marzano, M. Pellei, D. Colavito, S. Alidori, G. Gioia Lobbia, V. Gandin, F. Tisato and C. Santini, J. Med. Chem., 2006, 49, 7317-7324).